Hypoxia Inducible Factor 1 (HIF-1) is a transcription factor that controls expression of more than 60 target genes whose products are critical to many processes, including angiogenesis. For example, vascular endothelial growth factor (VEGF), the most important known regulator of angiogenesis, is upregulated by HIF-1. Active HIF-1 is composed of alpha (HIF-1α, 2α) and beta (HIF-1β) subunits that dimerize and bind to consensus sequences (hypoxia responsive elements, HREs) in the regulatory regions of the target genes. In normoxia, HIF-1 is hydroxylated and interacts with the von Hippel Lindau protein (pVHL), an E3 ubiquitin ligase subunit that targets HIF for degradation. In the absence of oxygen, HIF hydroxylation is inhibited, preventing binding to pVHL and leading to its intracellular accumulation. Increased levels of intracellular HIF-1α and HIF-2α have been associated with many aberrant vascularization processes.
Because of its critical role in angiogenesis, HIF-1 represents a promising target for the treatment and prevention of diseases and disorders associated with ocular neovascularization. Attempts to develop clinically useful therapies have been plagued by difficulty in administering and maintaining a therapeutically effective amount of HIF-1 inhibitors for an extended period of time. In addition, many HIF-1 inhibitors are cytotoxic, and exhibit significant side effects and/or toxicity, especially when administered to the ocular tissue.
In order to treat chronic diseases of the eye, there is a need for long acting methods for delivering HIF-1 inhibitors to the eye. Formulations which provide extended delivery of HIF-1 will minimize the potential for toxicity associated with the administration of many HIF-1 inhibitors. Formulations which provide extended delivery of HIF-1 will also sustain suppression of VEGF and other stimulators of angiogenesis, maximize efficacy, promote regression of neovascularization, and minimize the potential for catastrophic complications including subretinal hemorrhage. In addition, reducing the need for frequent injections will decrease the risk of endophthalmitis and decrease the burden of frequent clinic visits, a major hardship for patients and their families.
Therefore, it is an object of the invention to provide formulations of HIF-1 inhibitors with improved stability, safety, and efficacy.
It is also an object of the invention to provide drug formulations capable of effectively delivering therapeutic levels of one or more HIF-1 inhibitors for an extended period of time.
It is a further object of the invention to provide improved methods of treating or preventing diseases or disorders of the eye.